Osteoporosis

fracture

large-scale craniofacial defects and osteonecrosis are hot topics and are still underdiagnosed and undertreated in the clinic. It is urgent to understand the molecular mechanisms corresponding to the regulation of bone formation. CMTM3 (CKLF-like MARVEL transmembrane domain containing 3) connects the classic chemokine to the transmembrane 4 superfamily and plays an important role in intracellular vesicles transport

EGF receptor function maintenance and cancer development. However

its expression and function in bone remain unclear. In this paper

we found that the bone volume/total volume

trabecular number

trabecular thickness and bone surface area/bone volume of

Cmtm3

KO mice increased significantly

and trabecular separation and trabecular pattern factor decreased in

Cmtm3

KO mice compared with WT mice by microcomputed tomography. Moreover

the bone mineral content

bone mineral density

ultimate force and stiffness were also increased in

Cmtm3

KO mice. Using

in vitro

analysis

we showed that CMTM3 expression decreases during the differentiation of hBMSCs to osteoblasts. Knockdown of CMTM3 promoted ALP and mineralization of hBMSCs and facilitated osteoblastic differentiation with increasing RUNX2 expression. However

overexpression of CMTM3 got the opposite results. These results proved that CMTM3 was essential for osteogenic differentiation. In addition

knockdown of CMTM3 enhanced p-Erk1/2

but had no significant effect on p-Akt or p-STAT3 in hBMSCs and MC3T3-E1 cells. Taken together

our results indicated that Erk1/2 and RUNX2 pathways mediated by CMTM3 were involved in the process of osteogenic differentiation

and CMTM3 might be a new potential target in the treatment of bone formation-related disease.